Molecular mechanism of TGF-beta-induced apoptosis. Although TGF-beta is known to induce apoptosis in many cells, little information exists regarding the signaling pathways involved in apoptotic endpoints. We have demonstrated that Cdc2 and Cdk2 kinase activity transiently induced by TGF-beta phosphorylates retinoblastoma gene product (RB) as a physiological target in hepatoma cells and that this hyperphosphorylation of RB may trigger abrupt cell cycle progression, leading to irreversible cell death. In collaboration with Drs. Sarit Larich and Anita Roberts, we have identified a novel factor, ARTS, which is a mitochondrial septin-like protein derived from an alternative splicing of the H5 gene. Overexpression of ARTS in cells commits them to the TGF-beta -dependent apoptotic pathway. We have recently identified five alternatively spliced variants of the human septin H5.